Introduction

In October 2007, the US Food and Drug Administration (FDA) imposed a black box warning on the commercially available ultrasound contrast agents, citing spontaneous health care provider reports of several patient deaths and 190 "severe cardiopulmonary reactions" that had occurred in close temporal proximity to ultrasound contrast agent injection.¹ In addition, the FDA added multiple new disease state contraindications to ultrasound contrast agent administration including the following:

1. Worsening or clinically unstable heart failure
2. Acute myocardial infarction or acute coronary syndrome
3. Serious ventricular arrhythmia or high risk for arrhythmias due to QT prolongation
4. Respiratory failure
5. Severe emphysema, pulmonary emboli, or other conditions that cause pulmonary hypertension.

Of note, a mandated 30-minute monitoring period was also required for all examinations, including the ambulatory outpatient setting.

Initial Safety Studies

Beginning in 2008, a number of safety studies (mostly investigator initiated) were published. The first of these was a retrospective study of 18,671 hospitalized patients who underwent transthoracic echocardiography (12,475 patients underwent unenhanced echocardiography; 6,196 patients underwent echocardiography with the Lantheus Medical Imaging ultrasound contrast agent).² The mortality rate at 24 hours was similar between patients undergoing unenhanced echocardiography (0.37%) and patients who received the Lantheus ultrasound contrast agent (0.42%, p = 0.60) despite a higher prevalence of chronic obstructive pulmonary disease and lower baseline left ventricular ejection fraction and the fact that patients receiving the ultrasound contrast agent tended to be sicker with more days in the intensive care unit.

In a second large retrospective study³ of hospitalized patients utilizing the Premier Perspective database, acute (24-hour) mortality was compared between 58,254 patients who underwent echocardiography with an ultrasound contrast agent and 4,242,712 patients who underwent unenhanced echocardiography. Overall mortality was 1.08% in the unenhanced echocardiography arm and 1.06% in the ultrasound contrast agent patients. Multivariate logistic regression analysis revealed that patients undergoing contrast-enhanced echocardiography were 24% less likely to die within 24 hours.

A meta-analysis of 8 safety studies⁴ (including the 2 previously outlined studies) in which acute mortality was assessed (including 211,162 patients undergoing contrast echocardiography and 5,078,666 control patients undergoing unenhanced echocardiography) found that contrast echocardiography was associated with lower mortality (odds ratio 0.57, 95% confidence interval 0.32-1.01).

Studies Mandated By the FDA

On June 24, 2008, the FDA Cardio-Renal advisory panel was convened to review safety considerations for ultrasound contrast agents. Prior to this meeting, the FDA had also released details for six post-marketing studies to be conducted by Lantheus Medical Imaging and GE Healthcare.⁵ These included the following:

1. A right heart cardiac catheterization study in patients with either normal or elevated pulmonary artery systolic pressure at baseline to determine the effect of a clinically relevant dose of a ultrasound contrast agent on pulmonary artery systolic pressure and pulmonary vascular resistance
2. A retrospective study to determine the effect of ultrasound contrast agents on acute mortality in hospitalized patients receiving a ultrasound contrast agent
3. A clinical care registry to determine the incidence of serious adverse reactions in patients receiving ultrasound contrast agents

Results of these studies are shown in Table 1. There was no significant change in pulmonary artery systolic pressure or pulmonary vascular resistance in patients receiving ultrasound contrast agent from either Lantheus or GE.^6,7 The acute mortality database studies revealed no increase in acute mortality (in fact, acute mortality was actually lower in the Lantheus ultrasound contrast agent study).^8,9 And there were no serious adverse reactions in the ~1,000 patients enrolled in either of the clinical care registries.^10,11

Table 1: FDA-Mandated Post-Marketing Safety Studies for Ultrasound Contrast Agents

	Pulmonary Hemodynamic Study	Critically Ill Propensity-Matched Database	Routine Clinical Care Registry
Lantheus Medical Imaging	n = 326 No change in pulmonary artery pressure with ultrasound contrast agent No deaths or serious adverse events	n = 15,798 propensity-matched patients9 Hazard ratio = 0.683 (0.591-0.789)	n = 1,05310 No deaths or serious adverse events at 24 hours
GE Healthcare	n = 307 No change in pulmonary artery pressure with ultrasound contrast agent No deaths or serious adverse events	n = 2,884 propensity-matched patients8 Hazard ratio = 1.4 (0.965-2.030)	n = 1,03911 No deaths or serious adverse events

Potential for Rare Anaphylactic Reactions

In a meta-analysis by Khawaja and colleagues,⁴ the incidence of allergic and anaphylactic reactions was assessed in 110,500 patients who received an ultrasound contrast agent. Allergic reactions occurred in 11 patients (0.009%), and anaphylactic reactions occurred in 5 patients (0.004%). These reactions are believed to be secondary to a recently described type 1 hypersensitivity variant known as complement activation-related pseudo-allergy reactions.¹² In contrast to immunoglobulin E-mediated type 1 hypersensitivity reactions, in complement activation-related pseudo-allergy reactions no prior exposure is necessary, the reaction is typically milder or absent upon repeated exposure, spontaneous resolution often occurs, and there is a higher reaction rate among the general population;¹² women and "atopic" individuals (those with pre-existing food or environmental allergies) may be at higher risk.¹³ To mitigate this rare risk, sonographers, nurses, and physicians must recognize symptoms of serious allergy, which typically occur within minutes of contrast administration. In severe cases, these may include angioedema, bronchospasm, and hypotension. At Saint Luke's Mid America Heart Institute, we have placed "allergy kits" in close proximity to echocardiography machines. These kits include typical drugs used to treat allergic reactions: most importantly, automatic injectable epinephrine. In the very rare case (approximately 1:10,000 injections) of a true anaphylactic reaction, prompt administration of epinephrine may be lifesaving.

Current FDA Guidance

Based on investigator-initiated and manufacturer-sponsored safety studies, the FDA further revised product labeling for the commercially available ultrasound contrast agents in 2008 and 2011.¹⁴ In 2008, the disease state contraindications ("serious cardiopulmonary conditions") were downgraded from contraindications to use to warnings, and the 30-minute monitoring period was revised to include only patients with serious cardiopulmonary conditions or pulmonary hypertension. In 2008, the FDA allowed that serious adverse reactions are "uncommon" and typically "occur within 30 minutes of administration"; at that time, the 30-minute monitoring period was also deleted from product labeling. At present, the only remaining contraindications to ultrasound contrast agent administration are 1) previous hypersensitivity reactions, 2) intracardiac shunts (see below), and 3) intra-arterial injection.

Ultrasound Contrast Agent Safety in Patients With Shunts

Current product labeling for the commercially available ultrasound contrast agents contraindicates administration in patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts based on theoretical concerns for cerebral ischemia due to microvascular occlusion following injection.¹⁴ In 2013, the International Contrast Ultrasound Society published a position paper¹⁵ arguing that existing empiric evidence strongly supports the safety of ultrasound contrast agents in patients with intracardiac shunts, specifically in patients with patent foramen ovale (PFO). Evidence supporting this contention includes the following:

1. There have been no neurologic safety signals in large registries of ultrasound contrast agents. Based on population statistics, ~25% of patients in these registries likely had PFOs.^10,11
2. In a study of 39,020 patients who were administered commercially available ultrasound contrast agents, no transient ischemic attacks or strokes occurred in a subset of 418 patients with known PFOs.¹⁶
3. The FDA's contraindication of ultrasound contrast agents in patients with PFOs is contradicted by the FDA's guidance regarding macroaggregated albumin, which is used in ventilation/perfusion lung examinations. Macroaggregated albumin has a particle size of 10-150 mcm (with 90% in the 10-70 mcm range) and is potentially capable of occluding arterioles (20-30 mcm in diameter), but it carries only a "precaution" against use in patients with shunts. Ultrasound contrast agents (mean diameter 1.1-4.5 mcm; 95-98% < 10 mcm) are contraindicated in shunts and carry a boxed warning.¹⁵
4. Intravenous agitated saline is routinely and safely used for the detection of intracardiac shunts. In these studies, provocative maneuvers are utilized to potentiate right-to-left passage of large, unstable air microspheres.¹⁷

We believe this existing evidence strongly supports use of ultrasound contrast agents in patients with intracardiac shunts when clinically indicated, particularly in light of recent outcomes data that favors judicious use of ultrasound contrast agents (see below).

Balancing Safety With Efficacy

Any consideration of safety must be balanced against the potential for efficacy (in the case of a diagnostic test, the potential for clinical management change and possible improvement in outcome). Kurt and colleagues¹⁸ prospectively studied 632 patients with technically difficult echocardiograms, each of whom underwent a baseline unenhanced echocardiogram and a contrast-enhanced echocardiogram. The clinician caring for the patient was initially advised of the unenhanced echocardiogram findings, and management decisions were recorded. This same physician was subsequently advised that a contrast-enhanced echocardiogram had also been performed and was appraised of any incremental findings. Management changes based on this new data were then recorded. Overall, in about 1/3 patients, a subsequent procedure was avoided, a medication change was recommended, or both procedural and medication changes occurred. This effect was particularly pronounced in the surgical intensive care unit where 2/3 patients experienced a significant change in management. A cost-effectiveness assessment indicated a savings of $120 per patient (in spite of the additional cost incurred for the ultrasound contrast agent).

A retrospective propensity-matched study using the Premier Perspective database⁹ ultimately matched 16,217 hospitalized patients undergoing unenhanced echocardiography with 16,217 patients undergoing ultrasound contrast-enhanced echocardiography. Patients undergoing echocardiography with contrast had a lower mortality at 48 hours compared with patients undergoing unenhanced echocardiography (1.7 vs. 2.5%; odds ratio 0.66; 95% confidence interval, 0.54-0.80). The authors noted that although these data showed only an association between contrast-enhanced echocardiography and reduced mortality, the results were quite reassuring given previous anecdotal reports suggesting increased mortality with ultrasound contrast agent administration.

Safety Comparison With Other Cardiovascular Diagnostic Tests

The approximate 1:10,000 risk of anaphylactic reaction with ultrasound contrast agents must be placed in proper context. Virtually all cardiovascular testing is associated with some finite risk of adverse event. For example, exercise treadmill testing is associated with a 1:2500 risk of myocardial infarction or cardiac arrest.¹⁸ Single photon emission computed tomography is associated with a 1:1000 to 1:10,000 lifetime risk of fatal malignancy.^19,20 And coronary angiography is associated with a 1:1000 risk of mortality.²¹ Even cardiac magnetic resonance imaging (MRI) carries some potential risk. In a recent study of 13 patients who had each undergone at least 4 gadolinium-enhanced brain MRI examinations, gadolinium deposition was found in the brains of all at post-mortem examination (the clinical significance is unknown). No gadolinium deposition was noted in the brains of 10 control patients.²² In a separate study of 20 normal controls who underwent a chest cardiac MRI examination, a sharp uptick in double stranded DNA breaks was noted at 1 month following examination (the clinical significance of which is also unknown) and then returned to baseline values at 1 year.²³ Clinicians should be aware of the potential risks of all cardiac testing (including contrast echocardiography) and use each modality judiciously when results will likely impact patient management.

Conclusions

1. Following initial anecdotal reports of patient deaths and serious adverse reactions that occurred in close temporal relationship to ultrasound contrast agent injection, the U.S. FDA imposed a boxed warning and severe restrictions on the use of the commercially available ultrasound contrast agents. Subsequent investigator-initiated and manufacturer-sponsored safety studies documented an excellent safety profile for ultrasound contrast agents, including use in critically ill hospitalized patients.
2. There is a ~1:10,000 risk of anaphylactoid reaction immediately following ultrasound contrast agent reaction that is mediated by direct activation of complement (complement activation-related pseudo-allergy reaction). These very rare reactions are mitigated by prompt recognition and treatment with epinephrine. Auto-injectable epinephrine should be available at point of care for use by sonographers, nurses, and physicians.
3. Ultrasound contrast agent use is contraindicated in patients with intracardiac shunts (including PFOs), but experts have requested that the FDA rescind this contraindication. We believe the existing data support judicious use of ultrasound contrast agents in patients with PFOs.
4. In patients with baseline technically difficult echocardiograms, ultrasound contrast agent use alters the patient's management in 1/3 of patients (and 2/3 of patients in the surgical intensive care unit). This is associated with a reduction in downstream testing and a $120 per-patient savings. Ultrasound contrast agent use in hospitalized patients is associated with lower mortality, potentially due to earlier and more accurate diagnosis.
5. The risk of adverse events associated with ultrasound contrast agent administration compares quite favorably with other commonly performed cardiovascular tests and procedures, including exercise treadmill testing, stress single photon emission computed tomography examinations, coronary angiography, and cardiac MRI.

References

1. Main ML, Goldman JH, Grayburn PA. Thinking outside the "box"-the ultrasound contrast controversy. J Am Coll Cardiol 2007;50:2434-7.
2. Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies. J Am Coll Cardiol 2008;51:1704-6.
3. Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol 2008;102:1742-6.
4. Khawaja OA, Shaikh KA, Al-Mallah MH. Meta-analysis of adverse cardiovascular events associated with echocardiographic contrast agents. Am J Cardiol 2010;106:742-7.
5. Cardiovascular and Renal Drugs Advisory Committee. FDA Advisory Committee Briefing Document: Safety Considerations in the Development of Ultrasound Contrast Agents (FDA website). 06/24/2008. Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4369b1-01.pdf Accessed 04/19/2012.
6. Wei K, Main ML, Lang RM, et al. The effect of Definity on systemic and pulmonary hemodynamics in patients. J Am Soc Echocardiogr 2012;25:584-8.
7. Main ML, Grayburn PA, Lang RM, et al. Effect of Optison on pulmonary artery systolic pressure and pulmonary vascular resistance. Am J Cardiol 2013;112:1657-61.
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9. Main ML, Hibberd MG, Ryan A, Lowe TJ, Miller P, Bhat G. Acute mortality in critically ill patients undergoing echocardiography with or without an ultrasound contrast agent. JACC Cardiovasc Imaging 2014;7:40-8.
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11. Weiss RJ, Ahmad M, Villanueva F, et al. CaRES (Contrast Echocardiography Registry for Safety Surveillance): A prospective multicenter study to evaluate the safety of the ultrasound contrast agent definity in clinical practice. J Am Soc Echocardiogr 201225:790-5.
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15. Parker JM, Weller MW, Feinstein LM, et al. Safety of ultrasound contrast agents in patients with known or suspected cardiac shunts. Am J Cardiol 2013;112:1039-45.
16. Kalra A, Shroff GR, Erlien D, Gilbertson DT, Herzog CA. Perflutren-based echocardiographic contrast in patients with right-to-left intracardiac shunts. JACC Cardiovasc Imaging 2014;7:206-7.
17. Main ML, Feinstein SB, Feinstein LM, Grayburn PA, Wilson SR. Transient Ischemic Attack Caused by Contrast Echocardiography in a Patient with Platypnea-Orthodeoxia. Echocardiography 2016;33:165-6.
18. Kurt M, Shaikh KA, Peterson L, et al. Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort. J Am Coll Cardiol 2009;53:802-10.
19. Picano E. Sustainability of medical imaging. BMJ 2004;328:578-80.
20. Einstein AJ, Moser KW, Thompson RC, Cerqueira MD, Henzlova MJ. Radiation dose to patients from cardiac diagnostic imaging. Circulation 2007;116:1290-305.
21. Johnson LW, Lozner EC, Johnson S, et al. Coronary arteriography 1984-1987: a report of the Registry of the Society for Cardiac Angiography and Interventions. I. Results and complications. Cathet Cardiovasc Diagn 1989;17:5-10.
22. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology 2015;275:772-82.
23. Lancellotti P, Nchimi A, Delierneux C, et al. Biological Effects of Cardiac Magnetic Resonance on Human Blood Cells. Circ Cardiovasc Imaging 2015;8: e003697.

Keywords: Acute Coronary Syndrome, Albumins, Anaphylaxis, Angioedema, Arrhythmias, Cardiac, Arterioles, Blood Pressure, Bronchial Spasm, Cardiac Catheterization, Complement Activation, Confidence Intervals, Coronary Angiography, Critical Care, Critical Illness, DNA Breaks, Double-Stranded, Diagnostic Tests, Routine, Drug Labeling, Echocardiography, Emphysema, Epinephrine, Fluorocarbons, Foramen Ovale, Patent, Gadolinium, Heart Arrest, Heart Conduction System, Heart Failure, Hypertension, Pulmonary, Hypotension, Immunoglobulin E, Injections, Intra-Arterial, Intensive Care Units, Ischemic Attack, Transient, Logistic Models, Magnetic Resonance Imaging, Microspheres, Myocardial Infarction, Particle Size, Pharmaceutical Preparations, Point-of-Care Systems, Product Labeling, Pulmonary Artery, Pulmonary Disease, Chronic Obstructive, Research Personnel, Respiratory Insufficiency, Retrospective Studies, Stroke, Stroke Volume, Tomography, Emission-Computed, Single-Photon, United States Food and Drug Administration, Vascular Resistance

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